It is well established that development of conformational structure depends on amino acid sequence, although the exact relationship (which could make possible a precise prediction of native conformation from a knowledge of primary structure) remains unclear. It is widely accepted that native conformation develops from the randomly coiled chain of the denatured (or newly synthesized) protein, by a process of nucleation, whereby a progressive folding, governed by thermodynamic factors acting on the amino acid sequence, prevails until the native conformation is reached. This hypothesis rests on the assumption that the denatured protein exists predominantly in the randomly coiled state. However it has been observed in this and other laboratories that several proteins, denatured by reduction, contain secondary structure in amounts easily detectable by circular dichorism. These observations suggest that the existing hypothesis may have to be modified to account for the "denatured" structure and raise the questions as to how and at what stage the transition to native structure occurs. This problem is being attacked through a study of partial reduction of lysozyme under non-denaturing conditions. Thus far, the evidence obtained suggests that native secondary structure forms as a latter event, with native disulfide bond formation preceding it.